Disorders of purine metabolism in man occur in 5% of the population and may lead eventually to clinical disease in 1%. Although extrapolation of basic concepts derived from a study of model systems in lower organisms has been remarkably successful with regard to the regulation of purine metabolism, until recently little has been known about the actual mechanisms of control and uncontrol of this pathway in man. In the present investigation, the regulation of purine metabolism in human cells will be examined by a) a detailed study of kinetic and regulatory properties of certain crucial enzymes of purine metabolism isolated from human cells, b) an evaluation of mechanisms involved in controlling the rate of enzyme synthesis and degradation, and c) investigation of the specific nature and consequences of spontaneous mutations involving several enzymes in these pathways. During the tenure of this grant period specific methods of procedure will include immunoadsorbent chromatography, enzyme immunoprecipitation, molecular hybridization, and somatic cell hybridization. Results based on these studies in vitro and in cell culture will be integrated, when possible, with information derived from clinical studies in vivo. It is hoped that this broad but goal-directed approach will help not only to define the pathogenesis of aberrant control mechanisms in man but also that information of direct therapeutic relevance may emerge. BIBLIOGRAPHIC REFERENCES: Leyva, A., Holmes, E. W. and Kelley, W. N. Effect of 6-Mercaptopurine on Inosinic Acid Dehydrogenase in Cultured Human Fibroblasts. Biochem. Pharmacol., 25, 527, 1976. Kelley, W. N. Current therapy of gout and hyperuricemia. Hospital Practice. 11: 69-76, 1976.